CB1 Allosteric Inhibitors

Endocannabinoids are produced in the tissues where they interact with cannabinoid (CB) receptors to mediate appetite stimulation and mood modulation; the system can be over-active in certain diseases. The CB1 receptor emerged as a promising target for management of obesity and type 2 diabetes, but treatment with CB1 blockers caused psychiatric side-effects leading to suspension of their clinical use. These psychiatric side-effects are mediated by CB1 receptors in the brain. There is growing evidence for CB1 receptors in peripheral tissues that modulate obesity-related hormonal and metabolic abnormalities. Selective targeting of peripheral CB1 receptors would avoid the depression and anxiety associated with CB1 antagonists. We have discovered highly potent compounds which selectively 'tune down' endocannabinoid signaling. Current studies involve ensuring that these compounds are peripherally-restricted, thus avoiding psychiatric side-effects.

Funding: BBSRC Follow-on Fund

Project Team: Dr Iain Greig, Prof Ruth Ross and Dr Lynda Williams,